This application is the national phase of PCT/FR00/01123, filed Apr. 27, 2000.
The present invention relates to novel pyrrolo[3,4-b)quinoline derivatives of general formula I: 
in which X represents an oxygen atom or a sulfur atom, 
xe2x80x83represents a group of formula: 
R1 represents a lower alkyl radical containing from one to three carbon atoms, a lower cycloalkyl radical containing from three to six carbon atoms or R1 represents a lower alkyl radical linked to R4 to form a 6-atom ring containing 0, 1 or 2 unsaturations,
R2, R3, R4 and R5 represent, independently of each other, a hydrogen atom, a lower alkyl group containing from one to three carbon atoms, a lower cycloalkyl group containing from three to six carbon atoms or a phenyl group, the corresponding racemic mixtures, as well as the pure enantiomers thereof or mixtures thereof in all proportions and the pharmaceutically acceptable salts thereof.
The term xe2x80x9clower alkylxe2x80x9d means linear or branched C1-C3 alkyl residues chosen more particularly from methyl, ethyl, n-propyl, isopropyl and cyclopropyl groups.
When the derivatives comprise at least one asymmetric carbon, the present invention relates to the corresponding racemic mixtures, as well as to the pure enantiomers thereof or mixtures thereof in all proportions.
The therapeutically acceptable salts of the derivatives according to the invention are common organic or inorganic salts of the art, the hydrochlorides, tosylates, mesylates and citrates, as well as solvates such as the hydrates or hemihydrates of the compounds of general formula I.
The present invention more particularly relates to the derivatives of general formula I for which X preferably represents an oxygen atom or a sulfur atom.
Preferentially, R1 advantageously represents a lower alkyl radical, optionally linked to R4 to form a 6-atom ring, or a methyl, ethyl, n-propyl, isopropyl or cyclopropyl group.
Various pyrroloquinoline derivatives have been described in the prior art as synthetic intermediates by:
I. Pendrak, R. Winttrock, W. D. Kingsbury, J. Org. Chem, Vol. 60, No. 9, 1995, pages 2912-2915. T. Sugasowa, T. Toyoda, K. Saskura, Tetrahedron. Lett, No. 50, pages 5109-5112; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, J. L. Wood, Tetrahedron. Lett; Vol. 35, No. 32, pages 5763-5764; D. P. Curran, H. Liu, H. Josien, Tetrahedron Lett, Vol. 52, No. 35, pages 11385-11404; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, N. J. Sisti, J. L. Wood, Z. P. Zhung Tetrahedron. Lett; Vol. 37, No. 32, pages 5683-5686; D. L. Comins, J. K. Seha, J. Org. Chem, Vol. 61, No. 26, pages 9623-9624; A. I. Meyers et al., J. Org. Chem, Vol. 38, No. 8, 1993; S. Danishefsky, R. Volkmann, S. B. Horwitz, Tetrahedron Lett, No. 27, 1973, pages 2521, 2524; G. Stork, A. G. Schultz, J. Am. Chem. Soc, Vol. 93, No. 16, 1971; J. H. Rigby, D. M. Danca Tetrahedron Lett, Vol. 38, No. 28, 1997, pages 4969, 4972; M. Kitajima, S. Mosomoto, H. Takayama, N. Aimi, Tetrahedron. Lett, Vol. 38, No. 24, 1997, pages 4255-4258; M. Boch, T. Korth, J. M. Nelke, D. Pike, H. Radunz, Chem. Ber, 105, 1992, pages 2126-2142; M. Naoko, S. Takumchi, K. Yoshinori, S. Tako, Synlett, 1997, pages 298-300; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, N. J. Sisti, J. L. Wood, Z. P. Zhung Tetrahedron. Lett; Vol. 37, No. 32, pages 5679-5682; I. Pendrak, R. Winttrock, W. D. Kingsbury, J. Org. Chem., Vol. 60, No. 9, 1995, pages 2912-2915; J. Warneke, E. Winterfeldt, Chem. Ber, 105, 1972, pages 2120-2125.
T. Yaegashi et al. (CA. 157128, 960307); S. Sawada et al. (EP 296612, 881228); B. R. Vishnuvajjala et al. (U.S. Pat. No. 4,943,579, 900724); H. Akimoto et al. (EP 556585, 930825); E. Bombardelli et al. (EP 685481, 951206) and E. Bombardelli, L. Verotta (PCT INT Appl. WO 97 43, 290) have disclosed pyrroloquinoline derivatives which have therapeutic activity, although this activity is not hypnotic or sedative activity.
The present invention relates to the pyrrolo[3,4-b]quinoline derivatives of general formula I as defined above.
The derivatives of general formula I, for which X represents an oxygen atom, can be obtained directly by oxidizing the compounds of general formula II 
for which R1 and A are defined above, with oxygen in the presence of a base such as sodium hydride or potassium tert-butoxide, or with a periodate.
The sulfur analogs of general formula I (X=S) are obtained from the corresponding oxygen derivatives of formula I (X=O) by the action of Lawesson""s reagent, or by the action of phosphorus pentasulfide.
The examples which follow of preparations of derivatives according to the invention illustrate the present invention.
Examples of derivatives of general formula I, for which:
A) X represents an oxygen atom and 
xe2x80x83represents a group of formula 
when R4 and R5 each represent a hydrogen atom, are given in Table I below
when R1 and R4 are linked to form a ring corresponding to formula III 
are given in Table II below
B) X represents an oxygen or sulfur atom, and 
xe2x80x83represents a divalent radical of formula 
when R3, R4 and R5 each represent a hydrogen atom and R1 represents a methyl radical
are given in Table III below
when R1 and R4 are linked to form a ring corresponding to formula IV, R2 represents a hydrogen atom and X represents an oxygen atom 
are given in Table IV below